Drug Information

Drug (ID: DG00182) and It's Reported Resistant Information

• Name: Spiramycin
• Synonyms: Spiramycin; 8025-81-8; ST075006; Spiramycinum; Spiramycine; Provamycin; Sequamycin; Espiramicin; Rovamycin; Antibiotic 799; NSC-64393; RP 5337; Rovamycine; Prestwick_121; 5337 R.P.; Prestwick2_000745; Prestwick3_000745; AC1O4WG0; Spiramycin antibiotic complex; BPBio1_000804; SCHEMBL5032756; AKOS015896378; K430; SR-01000872632; SR-01000872632-1; I06-1973; Spiramycin, European Pharmacopoeia (EP) Reference Standard; Spiramycin from Streptomyces sp., VETRANAL(TM), analytical standard; Spiramycin, Pharmaceutical Secondary Standard
• Indication:
  In total 1 Indication(s)
  Bacterial infection [ICD-11: 1A00-1C4Z]; Approved; [1], [2], [3], [4], [5]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (4 diseases)
  Bacillus infection [ICD-11: 1C4Y]; [6]
  Bacterial infection [ICD-11: 1A00-1C4Z]; [1], [2], [3]
  Mycobacterial diseases [ICD-11: 1B2Z ]; [7]
  Streptococcal pharyngitis [ICD-11: 1B51]; [8]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (2 diseases)
  Actinomycetoma [ICD-11: 1C43]; [9]
  Bacterial infection [ICD-11: 1A00-1C4Z]; [10]
• Target: Bacterial 23S ribosomal RNA (Bact 23S rRNA); NOUNIPROTAC; [1]
• Formula: C43H74N2O14
• IsoSMILES: C[C@@H]1C/C=C/C=C/[C@@H]([C@@H](C[C@@H]([C@@H]([C@H]([C@@H](CC(=O)O1)O)OC)OC2C(C(C(C(O2)C)OC3CC(C(C(O3)C)O)(C)O)N(C)C)O)CC=O)C)OC4CCC(C(O4)C)N(C)C
• InChI: 1S/C43H74N2O14/c1-24-21-29(19-20-46)39(59-42-37(49)36(45(9)10)38(27(4)56-42)58-35-23-43(6,51)41(50)28(5)55-35)40(52-11)31(47)22-33(48)53-25(2)15-13-12-14-16-32(24)57-34-18-17-30(44(7)8)26(3)54-34/h12-14,16,20,24-32,34-42,47,49-51H,15,17-19,21-23H2,1-11H3/b13-12+,16-14+/t24-,25-,26 ,27 ,28 ,29+,30 ,31-,32+,34 ,35 ,36 ,37 ,38 ,39+,40+,41 ,42 ,43 /m1/s1
• InChIKey: ACTOXUHEUCPTEW-JMRHEKERSA-N
• PubChem CID: 6419898
• TTD Drug ID: D0F5OR
• DrugBank ID: DB06145

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Bacterial infection [ICD-11: 1A00-1C4Z]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ErmR rRNA adenine N6-methyltransferase (ERMR) [10]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Aeromicrobium erythreum infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Aeromicrobium erythreum strains AR18; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1807; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1848; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1849; 2041
• In Vitro Model: Aeromicrobium erythreum strains AR1850; 2041
• In Vitro Model: Aeromicrobium erythreum strains BD170; 2041
• Experiment for Molecule Alteration: Southern blotting assay
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: Using the Ery- strain AR1807 as a recipient for plasmid-directed integrative recombination, the chromosomal ermR gene (encoding 23S rRNA methyltransferase) was disrupted, ermR-disrupted strains AR1848 and AR1849 were highly sensitive to erythromycin and the other macrolide antibiotics. Phenotypic characterizations demonstrated that ermR is the sole determinant of macrolide antibiotic resistance in A. erythreum. AR18, AR1807, and AR1850 (Ery- Ermr) were resistant to clindamycin, erythromycin, spiramycin, and tylosin (some sensitivity totylosin was observed at high concentrations).

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Macrolide 2'-phosphotransferase II (MPHB) [1], [2], [3]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Bacterial infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AG100A; 562
• In Vitro Model: Escherichia coli DB10; 562
• In Vitro Model: Escherichia coli TOP10; 83333
• In Vitro Model: Escherichia coli XL1-Blue; 562
• In Vitro Model: Staphylococcus aureus RN4220; 1280
• Experiment for Molecule Alteration: Whole genome sequence assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Mph enzymes inactivate macrolides by phosphorylating the 2'-OH of the essential dimethylamino sugar, preventing it from binding the ribosome, and providing the chemical rationale for the resistance phenotype.

Mycobacterial diseases [ICD-11: 1B2Z ]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23S ribosomal RNA methyltransferase Erm (ERM39) [7]

• Molecule Alteration: Missense mutation; Putative initiation codon GTG>CTG
• Resistant Disease: Mycobacterium fortuitum infection [ICD-11: 1B2Z.2]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Mycobacterium peregrinum ATCC14467; 43304
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Mueller-Hinton (MH) broth assay
• Mechanism Description: The erm genes are a diverse collection of methylases that add one or two methyl groups to the adenine at position 2058 (Escherichia coli numbering) of the 23S rRNA; this modification impairs the binding of macrolides to ribosomes, and thus reduces the inhibitory activity of these agents.

Streptococcal pharyngitis [ICD-11: 1B51]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Macrolide-lincosamide-streptogramin B resistance protein (ERMA) [8]

• Molecule Alteration: Methylation; Macrolide-binding site on the ribosome
• Resistant Disease: Streptococcus pyogenes infection [ICD-11: 1A00-1C4Z]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Escherichia coli AG100A; 562
• Experiment for Molecule Alteration: PCR amplification and sequence alignments assay
• Experiment for Drug Resistance: Agar dilution method assay
• Mechanism Description: Macrolide resistance commonly occurs due to methylation of the macrolide-binding site on the ribosome by methyltransferases encoded by the erm group of genes, Induction of erm(A) occurs by translational attenuationInduction of erm(A) occurs by translational attenuation.

Actinomycetoma [ICD-11: 1C43]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: srmA open reading frame gimA (GIMA) [9]

• Molecule Alteration: Expression; Inherence
• Resistant Disease: Streptomyces ambbyaciens infection [ICD-11: 1C43.0]
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Escherichia coli; 668369
• In Vitro Model: Escherichia coli strain S17.1; 1227813
• In Vitro Model: Micrococcus luteus strain Cgr; 1270
• In Vitro Model: Micrococcus luteus strain DSM1790; 1270
• In Vitro Model: Streptomyces ambofaciens strain ATCC 23877; 278992
• In Vitro Model: Streptomyces ambofaciens strain OS41.99; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS41.99NP; 1954
• In Vitro Model: Streptomyces ambofaciens strain OS81; 1954
• In Vitro Model: Streptomyces lividans strain OS456; 1916
• Experiment for Molecule Alteration: DNA sequencing assay
• Experiment for Drug Resistance: Observation of growth inhibition zones assay
• Mechanism Description: With UDP-[14C]glucose as the cofactor, crude S30 extracts from OS456(pOS41.90) were tested on various macrolides. Among those, chalcomycin was the most active substrate. Methymycin, tylosin, pikromycin, and rosaramicin were four of the best substrates. Oleandomycin, josamycin, and carbomycin were glycosylated to a lesser extent. Macrolides that were found to be as poor substrates of GimA as lankamycin were erythromycin and angolamycin. Spiramycin was also a very poor substrate.

Bacillus infection [ICD-11: 1C4Y]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: 23S ribosomal RNA methyltransferase Erm34 (ERM34) [6]

• Molecule Alteration: Methylation; Ribosomal methylation
• Resistant Disease: Bacillus clausii infection [ICD-11: 1C4Y.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bacillus clausii ATCC 21536; 79880
• Experiment for Molecule Alteration: Cloning experiments and gene seqencing assay
• Experiment for Drug Resistance: Agar dilution assay
• Mechanism Description: This pattern of resistance generally due to the presence of an erm gene encoding a ribosomal methylase.

References

• Ref 1: Purification and characterization of macrolide 2'-phosphotransferase type II from a strain of Escherichia coli highly resistant to macrolide antibiotics. FEMS Microbiol Lett. 1992 Oct 1;76(1-2):89-94. doi: 10.1016/0378-1097(92)90369-y.
• Ref 2: Resistance phenotypes conferred by macrolide phosphotransferases. FEMS Microbiol Lett. 2007 Apr;269(2):317-22. doi: 10.1111/j.1574-6968.2007.00643.x. Epub 2007 Feb 16.
• Ref 3: The evolution of substrate discrimination in macrolide antibiotic resistance enzymes. Nat Commun. 2018 Jan 9;9(1):112. doi: 10.1038/s41467-017-02680-0.
• Ref 4: Cloning and nucleotide sequence of the mphB gene for macrolide 2'-phosphotransferase II in Escherichia coli. FEMS Microbiol Lett. 1996 Nov 1;144(2-3):197-202. doi: 10.1111/j.1574-6968.1996.tb08530.x.
• Ref 5: Expression of the mphB gene for macrolide 2'-phosphotransferase II from Escherichia coli in Staphylococcus aureus. FEMS Microbiol Lett. 1998 Feb 15;159(2):337-42. doi: 10.1111/j.1574-6968.1998.tb12880.x.
• Ref 6: Characterization of a new erm-related macrolide resistance gene present in probiotic strains of Bacillus clausii. Appl Environ Microbiol. 2004 Jan;70(1):280-4. doi: 10.1128/AEM.70.1.280-284.2004.
• Ref 7: Molecular basis of intrinsic macrolide resistance in clinical isolates of Mycobacterium fortuitum. J Antimicrob Chemother. 2005 Feb;55(2):170-7. doi: 10.1093/jac/dkh523. Epub 2004 Dec 8.
• Ref 8: Unusual resistance patterns in macrolide-resistant Streptococcus pyogenes harbouring erm(A). J Antimicrob Chemother. 2009 Jan;63(1):42-6. doi: 10.1093/jac/dkn432. Epub 2008 Oct 24.
• Ref 9: Characterization of a glycosyl transferase inactivating macrolides, encoded by gimA from Streptomyces ambofaciens. Antimicrob Agents Chemother. 1998 Oct;42(10):2612-9. doi: 10.1128/AAC.42.10.2612.
• Ref 10: Cloning vectors, mutagenesis, and gene disruption (ermR) for the erythromycin-producing bacterium Aeromicrobium erythreum. Appl Environ Microbiol. 1991 Sep;57(9):2758-61. doi: 10.1128/aem.57.9.2758-2761.1991.